The present invention relates to a dosage form that provides a controlled release of a low-solubility beneficial agent, or drug, to an environment of use.
Osmotic and hydrogel-driven drug delivery devices for the release of a drug have been known in the art for some time. Exemplary dosage forms have included a tablet comprising a semipermeable wall surrounding a compartment containing the drug and a layer of swellable hydrogel, with the drug being delivered through a passageway in the semipermeable wall by swelling of the hydrogel, as described in U.S. Pat. No. 4,327,725; another tablet comprising a wall permeable to an exterior fluid but impermeable to the drug, the wall surrounding a compartment containing two osmotic agents, two expandable polymers and the drug, as described in U.S. Pat. No. 4,612,008; drug dispersed in a swellable hydrogel matrix core that releases the drug by diffusion into the environment of use, as described in U.S. Pat. No. 4,624,848; a hydrogel reservoir containing a multiplicity of tiny pills wherein each tiny pill consists of a wall surrounding a drug core, as described in U.S. Pat. No. 4,851,232; and a two-layered tablet wherein one layer is drug mixed with a hydrogel and the other layer is a hydrogel, as described in U.S. Pat. No. 5,516,527.
While the conventional dosage forms described above are functional, nonetheless such dosage forms suffer from a variety of drawbacks. A controlled release dosage form should ideally deliver substantially all of the drug from the dosage form to the environment of use. However, a common problem encountered by osmotic and hydrogel-driven dosage forms, particularly when the drug has low aqueous solubility, is that residual drug is left in the tablet interior after the hydrogel or other swellable material has completely swelled. This residual drug is not available for absorption and, accordingly, such dosage forms require increased amounts of drug to compensate for the failure of the system to release all of the drug into the environment of use.
In addition, the controlled release dosage form must operate within certain size constraints, and yet be capable of delivering most or all of the drug to the environment of use. Dosage forms, particularly for humans, are limited in size, and are usually less than 1 gram, more preferably less than 700 mg in weight. However, for some types of drugs, the dose amount may make up to half or even more of the weight of the dosage form. The water-swellable materials that provide the delivery of the drug must in instances where the dose is high be capable of providing a highly efficient delivery of the drug, since very little of the dosage form may be available for the swellable material or other excipients.
In addition, it is often desired that the dosage form begin extruding drug relatively quickly upon entering the use environment. However, many delivery systems exhibit a time lag before extruding drug. This is particularly a problem when the drug has low aqueous solubility or is hydrophobic. Several techniques have been proposed to reduce the time lag, but each has its own drawback. One technique has been to provide high-permeability coatings by utilizing thin coatings around the dosage form. While this technique provides a quicker uptake of fluid, the thin coating lacks strength and often bursts in use or provides insufficient protection to the dosage form which becomes susceptible to damage during handling. Yet another technique has involved providing pores or one or more passageways that communicate with the water-swellable materials, but this often leads to unacceptable amounts of residual drug. Another technique involves coating the dosage form with an immediate release drug formulation, but this requires additional processing steps and provides a dosage form with two different release rates, which may be undesirable.
Yet another problem encountered with conventional osmotic and hydrogel-driven drug delivery systems is that such dosage forms often require the presence of osmagents. Osmagents are selected such that they generate an osmotic pressure gradient across the barrier of the surrounding coating. The osmotic pressure gradient drives the permeation of water into the tablet and the resulting buildup of sufficient hydrostatic pressure, which forces the drug through the delivery port. These osmagents increase the weight of the dosage form, thus limiting the amount of drug which may be contained in the dosage form. In addition, the presence of additional ingredients in the dosage form, such as osmagents, increases the costs of manufacture due to the need to insure uniform concentrations of the ingredients throughout the dosage form, and may have other drawbacks such as adverse effects on compression properties and on drug stability.
Accordingly, there is still a need in the art for a controlled release dosage form that results in a highly efficient delivery of drug to an environment of use with very little residual drug, that allows large drug loading so as to minimize the dosage size, that begins releasing drug soon after entering the environment of use, and that limits the number of necessary ingredients. These needs and others which will become apparent to one skilled in the art are met by the present invention, which is summarized and described in detail below.